Renin is a proteolytic enzyme having a molecular weight of about 40,000, produced and secreted by juxtaglomerular cells in the kidney. This acts on the plasma renin substrate, angiotensinogen, to yield decapeptide angiotensin I which is converted into angiotensin II by an angiotensin I converting enzyme.
It is well known that angiotensin II contracts the vascular smooth muscle and acts on the adrenal cortex to secrete the aldosterone which regulates salts and water balance. Accordingly, the reninangiotensin system plays an important role in hypertension. In fact, a specific inhibitor of angiotensin I converting enzyme has been investigated and developed as a practical medicament for hypertension. Thus, an effective inhibitor of renin has long been sought as an agent for treatment of hypertension, especially renin-associated hypertension. As a result, it has been found that certain peptides show a renin inhibitory effect, as described in Japanese Patent Applications (OPI) Nos. 155345/84, 227851/84 and 110661/84, (The term "OPI" as used herein refers to an unexamined Japanese patent application); Japanese Patent Publication No. 39149/83, Biochemical and Biophysical Research Communications, Vol. 118, pages 929-933, 1984; and European Patent Application Nos. 77029(A.sub.2), 77028(A.sub.2) and 81783(A.sub.2).
Of these prior art references, Japanese Patent Application (OPI) No.155345/84 discloses peptides represented by the following formula: ##STR1## wherein A represents a hydrogen atom, a phenyl group or 10,11-dihydro-5H-dibenzo[a,d]cycloheptenyl group, B represents --O--, --CH.dbd.CH--or --CH.sub.2 --, p and q may be the same or different and each represents an integer of from 0 to 3, D represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group or a phenylalkyl group, E represents a phenyl group, a cyclohexyl group or an isopropyl group, His represents an L-histidyl group, F represents a residual group of an amino acid such as an L-leucyl, an L-isoleucyl, an L-leucyl-L-phenylalanayl, an L-phenylalanyl-L-phenylalanyl and an L-alanyl-L-phenylalanyl group, and G represents a protective group attached to the terminal carbon atom of an amino acid, such as an amino group, an alkylamino group, an arylalkylamino group and an alkoxy group.
Japanese Patent Application (OPI) No. 227851/84 also discloses peptides represented by the following formula: ##STR2## wherein R.sup.5 CO-- represents an aliphatic acyl group, an aromatic acyl group, an aromatic aliphatic acyl group, a heterocyclic acyl group or a heterocyclic aliphatic acyl group, said acyl groups may be substituted with an amino, a protected amino, a hydroxy, a substituted dithio, an alkyl, an alkoxy, an alkoxycarbonyl, or a nitro group or a halogen atom; U represents a formyl group, or ##STR3## wherein R.sup.6 represents a hydrogen atom, an alkyl group, an alkyl group having a hydroxy, a mercapto, an amino, a carbamoyl, a formayl an aromatic ring or a heterocyclic ring substituent; Z represents a hydroxy, a mercapto or a formyl group, or U represents ##STR4## wherein R.sup.7 represents a hydroxy group or an alkyl group having a hydroxy, a mercapto, an amino, a carbamoyl, or a formyl group, or an aromatic ring or a heterocyclic ring substituent; His represents an L-histidyl group; C represents a carbon atom in the S-configuration, provided that, when U represents a formyl group, R.sup.5 CO-- does not represent a benzyloxycarbonyl-L-phenylalanyl group or a benzyloxycarbonylL-prolyl-L-phenylalanyl group.
The noted Biochemical and Biophysical Research Communications article discloses a peptide represented by the formula: ##STR5## wherein W represents a benzyloxycarbonyl group, an N-benzyloxycarbonyl-L-phenylalanyl group or an N-Benzyloxycarbonyl-3-(1naphthyl)-L-alanyl group, V represents a formyl group or a hydroxymethyl group and C represents a carbon atom in the L-configuration.
Japanese Patent Publication No. 39149/83 discloses peptides represented by the following formula: ##STR6## wherein R.sup.8 represents a methyl group, an ethyl group, a benzyl group, an adamantyl group or a benzyloxy group, Q represents an L-phenylalanyl group, an L-prolyl-L-phenylalanyl group or an L-histidyl-L-prolyl-L-phenylalanyl group, His represents an L-histidyl group, R.sup.9 represents an isopropyl group, and C represents a carbon atom in the L-configuration. These peptides show a renin inhibitory effect however, they are easily hydrolyzed by proteolytic enzymes of the gastorointestinal tract such as chymotrypsins. Therefore, these peptides have drawback that their renin inhibitory effect can not be expected with they are administered orally.
On the other hand, the peptides disclosed in the above European Patent Applications are polypeptides and have difficulties in their preparation and purification. Furthermore, they lose their pharmacological effects when administered orally similar to the peptides disclosed in the Japanese Patent Publication No. 39149/83, and their utility is thus limited.
Furthermore, the following peptide compounds were reported to have a human renin inhibitory activity in 106th Annual Meeting of the Pharmaceutical Society of Japan. (April, 1986) and The Meeting of Japanese Circulation Journal (March, 1986), respectively: ##STR7## wherein His represents an L-histidyl group. ##STR8## wherein His represents an L-histidyl group.
Thus, development of renin inhibitors which can display a sufficient therapeutic effect by oral administration has long been desired.